The mammalian peritoneal cavity drains into the circulatory blood system via two routes: splenic blood capillaries and the lymphatic system. Blood capillary drainage is believed to be primarily responsible for removal of lower molecular weight materials (below about 20,000 MW) from the peritoneal cavity, while the lymphatic system, which provides drainage through various lymph nodes and through the thoracic duct and other lymph ducts, is primarily responsible for removal of higher molecular weight (about 70,000 MW) materials. Experiments involving a number of therapeutic agents have demonstrated that the peritoneal cavity is cleared very rapidly of such agents when they are administered in their free chemical form. In such cases, the therapeutic agent is typically passed to the circulatory system and out of the body relatively quickly. Liposomal vesicles have been used to encapsulate various therapeutic agents, and it has been shown that such vesicles exhibit increased uptake by the liver and spleen upon intravenous injection, thus allowing targeting of encapsulated therapeutic agents to such organs.
Experiments in which liposomal vesicles have been injected into the peritoneal cavity have generally been directed toward increasing delivery of encapsulated agents to the lymphatic system. Thus, Ellens, et al., Biochim. Biophys. Acta, Vol. 674, pp.10-18 (1981), determined that encapsulated .sup.125 I-labeled poly (vinyl pyrrolidone) in sphingomyelin and cholesterol was taken up by the liver and spleen after intraperitoneal injection at a rate reduced by a factor of 2-3 compared to intravenous injection. Although the peritoneal cavity appeared to act as a reservoir for vesicles for some hours following intraperitoneal injection, clearance of the .sup.125 I label from the peritoneum led to less than 5% of the total initial injected dose remaining in that cavity after 12 hours. A number of researchers have verified increased lymphatic uptake following intraperitoneal injection of liposomal vesicles. Thus, Rahman, et al., Eur. J. Cancer Clin. Oncol., Vol. 20, No. 8, pp. 1105-1112 (1984), used multilamellar vesicles formulated from dipalmitoylphosphatidylcholine, cholesterol and stearylamine to encapsulate radiolabeled antitumor agent 1-.beta.-D-arabinofuranosylcytosine (ara-C) and determined that intraperitoneally-injected vesicles were more effective in treating mice lung tumors than intravenously-injected vesicles. This result was theorized to be attributable to sustained release of the ara-C, presumably due to an increased drug concentration in the lymphatics. Similarly, Hirano and Hunt, J. Pharm. Sci., Vol. 74, No. 9 (Sept. 1985), measured the biodistribution after intraperitoneal injection of small unilamellar vesicles and multilamellar vesicles (0.048-0.72 micron in diameter) composed of egg phosphatidylcholine, cholesterol, dipalmitoyl phosphatidic acid and alpha-tocopherol, and concluded that although absorption from the peritoneum to the lymphatics did not depend on vesicle size (more than about 50% of the injected radiolabel being absorbed from the peritoneum after 5 hours), retention within the lymphatics was dependent on size. The goal of this study was to increase lymphatic uptake as distinct from retaining the vesicles within the peritoneal cavity. Similar results were obtained by Parker et al., Cancer Res., Vol. 41, pp. 1311-1317 (April 1981), wherein adriamyci encapsulated in dipalmitoyl-phosphatidylcholine-cholesterolstearylamine vesicles (diameter less than 0.6 micron) were shown to be accumulated in the lymph nodes draining the peritoneal cavity.
Earlier work by Parker et al., Drug Metab. Dispos., Vol. 10, pp. 40-46 (1982) showed that liposomes composed of egg phosphatidylcholine, cholesterol, stearylamine and radiolabelled dipalmitoyl-phosphatidylcholine and used to encapsulate ara-C (size apparently less than 0.6 micron) exhibited increased lymphatic uptake after intraperitoneal injection compared to free ara-C, as well as 40-60% retention of radiolabelled material in peritoneal washings taken 6 hours after injection. Patel and Ryman noted in Knight (ed), Liposomes: From Physical Structure to Therapeutic Applications, Chapter 15, pp. 409-440 at 425 (Elsevier/North-Holland Biomedical Press 1981) that multilamellar vesicles too large to enter the lymphatics may act as a "depot" for intrapped drugs at the site of intraperitoneal injection. However, the later studies of Hirano and Hunt, discussed above, showed that MLV clearance from the peritoneal cavity appeared to be size independent for those vesicles studied (up to about 0.72 micron in diameter). Moreover, the extent of retention in the peritoneal cavity is not shown to be of any therapeutic significance.
U.S. Pat. No. 4,427,649, Dingle et al. (Jan. 24, 1984) proposes the use of compositions comprising anti-inflammatory steroid derivatives encapsulated in liposomes formed from dimyristoyl-, dipalmitoyl- or distearoylphosphatidylcholines (diameter greater than about 0.1-0.5 micron) to treat inflammatory conditions involving an enclosed cavity, as for example intra-articular joints. Although use within the peritoneum is proposed, this speculation is never tested and there is no indication that the problem of lymphatic drainage was even recognized in the intraperitoneal administration context. For example, it has been noted by Poste et al. in Gregoriadis (ed.), Liposome Technology, Volume III, chapter 1, pp. 2-26 at 20 (CRC Press, Inc. 1984) that the problem of sustaining liposomal residence in the peritoneal cavity is more difficult than in joints, where liposomes are known to persist for considerable times.